Elsamitrucin is an antibiotic anticancer agent exhibiting in vitro cytotoxicity against murine and human tumor cell lines and in vivo antitumor activity against murine leukemias, murine solid tumors and human tumor xenografts.
Elsamitrucin's structure is: ##STR1##
Its preparation and properties are set out in U.S. Pat. Nos. 4,518,589 and 4,572,895. The disclosures of these documents are hereby incorporated herein by reference.
The drug is highly effective. However, its use in parenteral formulations is problematic because of its low solubility (&lt;100 mcg/mL) in water and water/alcohol solutions. Attempts to solubilize the drug have led to the preparation of salts of same.
In Investigational New Drugs, 7:175-8 (1989), J. E. Schuring et al discussed the antitumor activity of elsamitrucin (also called "elsamicin" and "elsamicin A"). The in vitro and in vivo activity of the drug, as well as properties of its lactate and succinate salts are disclosed.
Lyophilized 1:1 elsamitrucin succinate was described at the American Association of Pharmaceutical Scientists (AAPS), 5th Annual Meeting, Nov. 4-8, 1990. The salt was in a solid lyophilized formulation containing mannitol as a bulking agent. The solid is reconstituted with Sterile Water for Injection prior to use. The resultant solutions are stable for 48 hours at 25.degree. C.
In a preferred embodiment, a stable ready-to-use formulation is provided. It contains a 1:1 elsamitrucin: succinic acid in-situ salt solution(5 mg elsamitrucin base/mL) in water, with pH adjustment to 4 using hydrochloric acid and 0.1% acetone sodium bisulfite stabilizer. In a highly preferred embodiment, the solution is purged with nitrogen (N.sub.2) and the headspace gas is N.sub.2. This solution has a projected shelf life of at least 18 months at about 15.degree. C. to about 30.degree. C.
Advantages
The solutions of the invention have several advantages over those of the prior art. They are liquid, so that they can be used as is or they can be diluted with one or more carrier(s).
Depending upon the stabilizer employed, the solutions retain up to 96% potency after 3 months at 50.degree. C. Their controlled room temperature (15.degree. C.-30.degree. C.) stability is even greater.
These and other advantages of the invention will be better understood after consideration of the following drawings, specification and claims.